Process for preparing an aqueous solution of a methylcellulose

ABSTRACT

A process for preparing an aqueous solution of a methylcellulose having anhydroglucose units joined by 1-4 linkages wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.36 or less, wherein s23 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups and wherein s26 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups, comprises the step of mixing the methylcellulose with an aqueous liquid at a temperature of not higher than 10° C. at a shear rate of at least 1000 s −1 .

FIELD

The present invention relates a process for preparing an aqueoussolution of a certain methylcellulose and to aqueous solutions of acertain methylcellulose that are useful as food additives or as foodreplacement, for example in methods for inducing satiety.

INTRODUCTION

Conventionally, methylcellulose has been found to be very useful in avariety of applications, providing thickening, freeze/thaw stability,lubricity, moisture retention and release, film formation, texture,consistency, shape retention, emulsification, binding, gelation, andsuspension properties. One unusual property of methylcellulose is thatit is known to exhibit reverse thermal gelation in water, in otherwords, aqueous methylcellulose materials are soluble at coolertemperatures and gel at warmer temperatures. Most grades ofmethylcellulose gel at around 50 to 60° C.

A grade of methylcellulose that gels in water at a relatively lowtemperature, 38 to 44° C., is generally available under the trade nameMETHOCEL SG or SGA (The Dow Chemical Company). U.S. Pat. No. 6,235,893teaches methylcelluloses that gel as low as 31° C. Methylcellulosesdescribed in U.S. Pat. No. 6,235,893, when dissolved in water, have anenhanced gel strength. One way of measuring the gel strength is the gelpuncture force.

Specific grades of methylcellulose have been described that are usefulfor inducing satiety in an individual. International Patent ApplicationWO2011/139763 discloses a cold aqueous medicament or food supplement,that when ingested and warmed by an individual, forms a gel mass in theindividual's stomach, said gel mass consisting essentially ofmethylcellulose and water. The methylcellulose utilized in the Examplesof WO2011/139763 has a gelation temperature of 28° C.

In nutritional terms, satiety is a complex response, involving both anindividual's emotional and physical perception of whether or not theyhave ingested enough. Satiety can be observed as a reduction of appetiteimmediately following consumption, or as a reduction of food intake atthe next meal. As can be appreciated, control of satiety is mostrelevant in cases where an individual consumes more calories than arenecessary. Inducing satiety can be useful for causing a reduced caloricintake, i.e., for aesthetic purposes (i.e., as a slimming aid for weightloss or weight management) or for medical treatment (for example, fortreating obesity). For purposes of this specification, “satiety” refersto a net reduction of caloric intake, or a robust reduction in hungerresponses, by an individual. When satiety is induced by a specific gradeof methylcellulose, it is often thought to arise at a sufficient gelfracture force F_(GF)(37° C.).

While the methylcelluloses described in WO2011/139763 and in U.S. Pat.No. 6,235,893 are very useful due to their low gelation temperatures inwater, unfortunately they are difficult to fully hydrate, i.e., to bringthem into aqueous solution with an ability to deliver sufficient gelfracture force when warmed to 37° C. As described in WO2011/139763, toobtain a 2% aqueous solution of a methylcellulose which has a gelationtemperature of only 28° C. a corresponding amount of ground and driedmethylcellulose is added to water at room temperature while stirring at500 rpm, the blend is cooled to about 1.5° C. and the speed of thestirrer is reduced stepwise: 500 rpm for 15 min, then 400 rpm for 10min, then 200 rpm for 10 min, and then 100 rpm for 5 h. The solution isthen stored over night at about 0.5 to about 1° C. Unfortunately, suchprocess takes unduly long and requires an undue amount of cooling.Methylcellulose that is commercially available under the trade nameMETHOCEL SG or SGA (The Dow Chemical Company) and that gels in water atsomewhat higher temperatures, usually at 38 to 44° C., can be broughtinto aqueous solution at somewhat higher temperatures, e.g., attemperatures of up to 10° C., but also for this type of methylcellulosecooling is required and the process to bring the methylcellulose intoaqueous solution also takes unduly long.

Accordingly, one object of the present invention is to provide a moreefficient process for preparing an aqueous solution of a methylcellulosewhich has a low gelation temperature.

It has been suggested by skilled artisans that addition of specifictypes of compounds to drinks can enhance suppression of hunger when thecompounds form strong gastric gels after consumption of the drinks.Strong gels can be formed at a temperature of an individual's normalbody temperature by including in food high concentrations, e.g,concentrations of 5 weight percent or more, of a gellingmethylcellulose, but high concentrations of the gelling methylcelluloseare not accepted by many consumers for organoleptic reasons,specifically the slightly slimy texture when the gelling methylcelluloseis incorporated in food at high concentrations. Accordingly, there isstill a need that i) the gel strength of an aqueous gelled compositioncomprising an above-mentioned methylcellulose can be increased withoutsubstantially increasing the concentration of the methylcellulose in thecomposition and/or that ii) the concentration of the methylcellulose inthe composition can be decreased without substantially decreasing thegel fracture force F_(GF)(37° C.) of the aqueous gelled composition.

The co-pending International Patent Application PCT/US12/059714, filed11 Oct. 2012, teaches that the gel strength of an aqueous gelledcomposition comprising an above-mentioned methylcellulose can besignificantly increased if a protein is included in the composition suchthat the weight ratio w(protein)/w(methylcellulose) is at least 0.7/1.0.However, the presence of proteins is not desired in all food, foodingredients or food supplements. Accordingly, there is still the needthat the gel strength of a protein-free aqueous gelled composition canbe increased.

SUMMARY

Surprisingly, it has been found that an aqueous solution of amethylcellulose which has a low gelation temperature can be producedwithout storing the mixture of water and methylcellulose for a long timeat a temperature which is considerably lower than the gelationtemperature of the methylcellulose if the methylcellulose is contactedwith water under high shearing as defined below. It has even moresurprisingly been found that the gel strength, e.g. the gel punctureforce or the gel fracture force F_(GF)(37° C.), of an aqueous solutionof a certain methylcellulose as defined below can be increased by thisprocess.

Accordingly, one aspect of the present invention is a process forpreparing an aqueous solution of a methylcellulose having anhydroglucoseunits joined by 1-4 linkages wherein hydroxy groups of anhydroglucoseunits are substituted with methyl groups such that s23/s26 is 0.36 orless, wherein s23 is the molar fraction of anhydroglucose units whereinonly the two hydroxy groups in the 2- and 3-positions of theanhydroglucose unit are substituted with methyl groups and wherein s26is the molar fraction of anhydroglucose units wherein only the twohydroxy groups in the 2- and 6-positions of the anhydroglucose unit aresubstituted with methyl groups, wherein the process comprises the stepof mixing the methylcellulose with an aqueous liquid at a shear rate ofat least 1000 s⁻¹.

Another aspect of the present invention is a protein-free aqueoussolution of an above-mentioned methylcellulose, wherein theconcentration of the methylcellulose is from 0.2 to 2.5 weight percentand the aqueous solution has a gel fracture force F_(GF)(37° C.) of i)at least 1.4 N when the concentration of the methylcellulose is from 0.2to 0.4 weight percent, ii) at least 2.0 N when the concentration of themethylcellulose is from 0.5 to 0.7 weight percent, iii) at least 2.5 Nwhen the concentration of the methylcellulose is from 0.8 to 1.0 weightpercent, iv) at least 3.5 N when the concentration of themethylcellulose is from 1.1 to 1.3 weight percent, v) at least 4.5 Nwhen the concentration of the methylcellulose is from 1.4 to 1.6 weightpercent, vi) at least 9.0 N when the concentration of themethylcellulose is from 1.7 to 1.9 weight percent, vii) at least 11.0 Nwhen the concentration of the methylcellulose is from 2.0 to 2.2 weightpercent or viii) at least 13.0 N when the concentration of themethylcellulose from is 2.3 to 2.5 weight percent, based on the totalweight of the aqueous solution.

Yet another aspect of the present invention is a medicament, food, foodingredient or food supplement which comprises or is made of theabove-mentioned aqueous solution of the methylcellulose.

Yet another aspect of the present invention is a method of reducingcaloric intake, inducing satiety or reversibly reducing stomach voidvolume in an individual or of treating gastric ulcers, gastro-esophagealreflux disease, or obesity, or of aiding slimming, weight loss, orweight control in a non-obese individual, which comprises the step ofadministering to said individual the above-mentioned aqueous solution orthe above-mentioned medicament, food, food ingredient or foodsupplement.

DESCRIPTION OF EMBODIMENTS

The process of the present invention relates to a high-shear process forpreparing an aqueous solution of a methylcellulose. The aqueous solutionof the methylcellulose may be liquid-like or solid-like. A coldliquid-like aqueous-solution form of the present invention, which has atemperature of about 0.5 to 10° C., transforms into its warm solid-likephysical-gel form, as its temperature approaches body temperature (37°C.), and at body temperature it meets or exceeds the target gel fractureforce F_(GF)(37° C.) relevant to satiety applications as defined furtherbelow.

The methylcellulose used for preparing the aqueous solution of thepresent invention has anhydroglucose units joined by 1-4 linkages. Eachanhydroglucose unit contains hydroxyl groups at the 2, 3, and 6positions. Partial or complete substitution of these hydroxyls createscellulose derivatives. For example, treatment of cellulosic fibers withcaustic solution, followed by a methylating agent, yields celluloseethers substituted with one or more methoxy groups. If not furthersubstituted with other alkyls, this cellulose derivative is known asmethylcellulose. An essential feature of the present invention is theuse of a specific methylcellulose wherein hydroxy groups ofanhydroglucose units are substituted with methyl groups such thats23/s26 is 0.36 or less, preferably 0.33 or less, more preferably 0.30or less, most preferably 0.27 or less, or 0.26 or less, and particularly0.24 or less or 0.22 or less. Typically s23/s26 is 0.08 or more, 0.10 ormore, 0.12 or more, 0.14 or more, or 0.16 or more. The term “whereinhydroxy groups of anhydroglucose units are substituted with methylgroups” as used herein means that the hydrogen in a hydroxy group isreplaced by a methyl group to form a methoxy group.

In the ratio s23/s26, s23 is the molar fraction of anhydroglucose unitswherein only the two hydroxy groups in the 2- and 3-positions of theanhydroglucose unit are substituted with methyl groups and s26 is themolar fraction of anhydroglucose units wherein only the two hydroxygroups in the 2- and 6-positions of the anhydroglucose unit aresubstituted with methyl groups. For determining the s23, the term “themolar fraction of anhydroglucose units wherein only the two hydroxygroups in the 2- and 3-positions of the anhydroglucose unit aresubstituted with methyl groups” means that the two hydroxy groups in the2- and 3-positions are substituted with methyl groups and the6-positions are unsubstituted hydroxy groups. For determining the s26,the term “the molar fraction of anhydroglucose units wherein only thetwo hydroxy groups in the 2- and 6-positions of the anhydroglucose unitare substituted with methyl groups” means that the two hydroxy groups inthe 2- and 6-positions are substituted with methyl groups and the3-positions are unsubstituted hydroxy groups.

Formula I below illustrates the numbering of the hydroxy groups inanhydroglucose units.

The methylcellulose preferably has a DS(methyl) of from 1.55 to 2.25,more preferably from 1.65 to 2.20, and most preferably from 1.70 to2.10. The degree of the methyl substitution, DS(methyl), also designatedas DS(methoxyl), of a methylcellulose is the average number of OH groupssubstituted with methyl groups per anhydroglucose unit.

The determination of the % methoxyl in methylcellulose (B) is carriedout according to the United States Pharmacopeia (USP 34). The valuesobtained are % methoxyl. These are subsequently converted into degree ofsubstitution (DS) for methyl substituents. Residual amounts of salt havebeen taken into account in the conversion.

The viscosity of the methylcellulose is preferably at least 50 mPa·s,more preferably at least 200 mPa·s, even more preferably at least 400mPa·s or at least 500 mPa·s and most preferably at least 600 mPa·s or atleast 700 mPa·s, when measured as a 2 wt.-% aqueous solution at 5° C. ata shear rate of 10 s⁻¹. The viscosity of the methylcellulose ispreferably up to 30000 mPa·s, more preferably up to 10000 mPa·s, evenmore preferably up to 7000 mPa·s and most preferably up to 6000 mPa·s orup to 3000 mPa·s or up to 2000 mPa·s, or even only up to 1500 mPa·s,when measured as indicated above.

In the process for preparing an aqueous solution, the above describedmethylcellulose is typically utilized in ground and dried form. Themethylcellulose is mixed with an aqueous liquid at a shear rate of atleast 1000 s⁻¹, preferably at least 5000 s⁻¹, more preferably at least10000 s⁻¹, even more preferably at least 15000 s⁻¹, and most preferablyat least 25000 s⁻¹ or even at least 35000 s⁻¹. The shear rate istypically up to 150,000 s⁻¹, more typically up to 100,000 s⁻¹, even moretypically up to 80000 s⁻¹, and most typically up to 60,000 s⁻¹. Evenhigher shear rates can be applied, but they do not provide anyadditional advantages. The term “shear rate” is the commonly used termfor the more specific term “shear strain rate”.

The above-mentioned shear rate can be obtained in a high-shear device,such as a high-shear mixer, also known as rotor-stator mixer orhomogenizer, high-shear mill or high-shear pump. A high-shear devicecommonly comprises a rotor in combination with a stationary part of theshear device, also referred to as “stationary”, such as a stator orhousing. The stationary creates a close-clearance gap between the rotorand itself and forms a high-shear zone for materials in this gap. Thestationary can include single or multiple rows of openings, gaps orteeth to induce a kind of shear frequency and increased turbulentenergy.

One metric for the degree or thoroughness of mixing is the shearingforce generated by a mixing device with a high tip speed. Fluidundergoes shear when one area of fluid travels with a different velocityrelative to an adjacent area. The tip speed of the rotor is a measure ofthe kinetic energy generated by the rotation according to the formula:Tip speed=rotation rate of rotor×rotor circumference.

In the process of the present invention the rotation rate of the rotoris preferably at least 1000 rpm, more preferably at least 1200 rpm, evenmore preferably at least 1500 rpm, most preferably at least 2000 rpm,and particularly at least 4000 rpm. The rotation rate is generally up to50,000 rpm, typically up to 40,000 rpm, more typically up to 30,000 rpm,and most typically up to 20,000 rpm or up to 10,000 rpm. Even higherrotation rates can be applied, but they do not provide any additionaladvantages.

The shear rate is based on the inverse relationship between the gapdistance between the rotor and the stationary part of the shear devicewhich is commonly referred to as the stator or housing. In the case thehigh-shear device is not equipped with a stator, the inner wall of avessel serves as a stator.Shear rate=Tip speed/gap distance between outer diameter of rotor andstationary.In case the gap distance between the outer diameter of the rotor and thestationary is not constant over the entire size of the high-sheardevice, the smallest gap distance is determined.

The process of the present invention is preferably conducted in a sheardevice running at a tip speed of at least 2 m/s, preferably at least 4m/s, more preferably at least 6 m/s, and most preferably at least 8 m/s.The tip speed is generally up to 100 m/s, typically up to 60 m/s, andmore typically up to 40 m/s.

A further shearing is induced by a velocity difference between the tipvelocity of the fluid at the outside diameter of the rotor and thevelocity at the centre of the rotor.

High-shear devices are also called high-shear mixers and encompassdifferent geometries such as colloid mills, toothed-devices,axial-discharge and radial-discharge rotor stator mixers (Atiemo-Obeng,V. A. and Calabrese, R. V., 2004. “Rotor-stator mixing devices” inHandbook of Industrial Mixing: Science and Practice, E. L. Paul, V. A.Atiemo-Obeng and S. M. Kresta, John Wiley & Sons, Hoboken, N.J., USA.).The high-shear device can be used in a continuous or batch operation.

It has surprisingly been found that by the process of the presentinvention less cooling is required to achieve an aqueous solution of theabove-described methylcellulose which after warming has the same gelstrength as an aqueous solution of the same methylcellulose and the sameconcentration, but which is produced by a known low-shear process.Alternatively, when the dissolution of the methylcellulose in theaqueous liquid is carried out by the high-shear process of the presentinvention at the same temperature as by a known low-shear dissolutionprocess, generally the process of the present invention provides anaqueous solution of methylcellulose which has a considerably higher gelstrength after warming than when applying a low-shear process. Thepreferred temperature for preparing the aqueous solution of themethylcellulose according to the process of the present inventionsomewhat depends on the specific methylcellulose to be dissolved.

In one embodiment of the invention hydroxy groups of anhydroglucoseunits are substituted with methyl groups such that the s23/s26 of themethylcellulose is 0.27 or less, preferably 0.26 or less, morepreferably 0.24 or less or even 0.22 or less. In this embodiment of theinvention s23/s26 of the methylcellulose typically is 0.08 or more, 0.10or more, 0.12 or more, 0.14 or more, or 0.16 or more. Suchmethylcellulose is generally mixed with an aqueous liquid while coolingthe aqueous mixture to a temperature of not higher than 10° C.,preferably not higher than 8° C., more preferably not higher than 6.5°C., and most preferably not higher than 5° C. Usually the aqueousmixture has a temperature of 0.5 to 2° C. When the aqueous mixture iscooled to the same temperature as in the prior art dissolutionprocesses, such as disclosed in WO2011/139763, but a high shear rate ofat least 1000 s⁻¹, preferably at least 5000 s⁻¹, more preferably atleast 10000 s⁻¹, even more preferably at least 15000 s⁻¹, and mostpreferably at least 25000 s⁻¹ or even at least 35000 s⁻¹ is applied,surprisingly an aqueous solution of methylcellulose is obtained whichafter warming has a considerably higher gel fracture force F_(GF)(37°C.) than when applying a low-shear process as described in the priorart. Moreover, it has surprisingly been found that in the process of thepresent invention less cooling is required than in a known low-shearprocess to achieve an aqueous solution of the above describedmethylcellulose of the same gel fracture force F_(GF)(37° C.). Forexample, an aqueous solution of the same gel fracture force F_(GF)(37°C.) after warming can be obtained when cooling the aqueous liquid to 10°C. as is obtained in a low-shear process when the aqueous liquid iscooled to 2° C. This results in a considerable savings in energy.

In another embodiment of the invention hydroxy groups of anhydroglucoseunits are substituted with methyl groups such that the s23/s26 of themethylcellulose is more than 0.27 and up to 0.36, preferably more than0.27 and up to 0.33, and most preferably more than 0.27 and up to 0.30.Such methylcellulose is generally mixed with an aqueous liquid at atemperature of from 5 to 25° C., preferably from 11 to 23° C., morepreferably from 13 to 21° C. When the methylcellulose is mixed with theaqueous liquid at a temperature of from 11 to 23° C., more preferablyfrom 13 to 21° C., surprisingly an aqueous solution of methylcelluloseis obtained which has considerably higher gel strength, measured as gelpuncture force at a temperature of 80° C., than when applying a knownlow-shear process. Moreover, it has surprisingly been found that in theprocess of the present invention no cooling or considerably less coolingis required than in a known low-shear process to achieve an aqueoussolution of the methylcellulose of a similar gel puncture force. Forexample, in the high-shear process of the present invention an aqueoussolution of about the same gel puncture force can be obtained at atemperature of 15-20° C. as is obtained in a low-shear process when theaqueous liquid and the methylcellulose are mixed and cooled to about 12°C. This results in a considerable savings in energy.

Moreover, the dissolution process of the present invention is completedin a much shorter time period that the process described inWO2011/139763. Usually the dissolution process of the present inventionis completed in less than 30 minutes, typically in less than 15 minutes,more typically in less than 10 minutes, and most typically in 5 minutesor less.

The amount of the aqueous liquid is advantageously chosen for preparingthe aqueous solution that the amount of the methylcellulose is from 0.2to 2.5 weight percent, preferably from 0.5 to 2.2 weight percent, morepreferably from 0.8 to 2.2 weight percent, and most preferably from 0.8to 1.9 weight percent, based on the total weight of the aqueoussolution. The major part of the aqueous liquid is water. Water may bemixed with a minor amount of one or more organic liquids which arepreferably physiologically acceptable, such as ethanol or one or moreanimal or vegetable oils, but the total amount of organic liquids ispreferably not more than 20 percent, more preferably not more than 10percent, even more preferably not more than 5 percent, based on thetotal weight of water and organic liquid. Most preferably, the aqueousliquid is not mixed with an organic liquid.

Optional ingredients may be added to the methylcellulose or the aqueousliquid before or during the high shearing process described above.Alternatively, optional ingredients may be added after the preparationof the aqueous solution. The amount of the optional ingredientsgenerally is not more than 20 percent, preferably not more than 10percent, more preferably not more than 5 percent, and most preferablynot more than 2 percent, based on the total amount of the aqueoussolution of methylcellulose. Examples of optional ingredients areartificial sweeteners, colorants, flavorants, antioxidants,preservatives, salts, such as sodium chloride, or combinations thereof.Preferably the aqueous solution does not comprise a significant amountof optional ingredients that have a significant caloric value uponconsumption by an individual. Preferably the aqueous solution of thepresent inventions is substantially free of calories. Furthermore, otherthan the methylcellulose described above, preferably the aqueoussolution does not comprise any optional ingredient that acts as athickener or as a gelling agent or that has otherwise an impact on thegel fracture force F_(GF)(37° C.) in an amount to increase the gelfracture force F_(GF)(37° C.). The sum of the methylcellulose and wateris generally at least 70 percent, preferably at least 80 percent, morepreferably at least 90, and most preferably at least 95 percent, basedon the total weight of the aqueous solution of the above-describedmethylcellulose.

In one embodiment of the invention the high-shear process describedabove provides an aqueous solution of a methylcellulose wherein hydroxygroups of anhydroglucose units are substituted with methyl groups suchthat s23/s26 is 0.27 or less, wherein the concentration of themethylcellulose is from 0.2 to 2.5, preferably from 0.5 to 2.2, morepreferably from 0.8 to 2.2, even more preferably from 0.8 to 1.9, andmost preferably from 1.0 to 1.9 weight percent, based on the totalweight of the aqueous solution, and the aqueous solution has a gelfracture force F_(GF)(37° C.) of

i) at least 1.4 N, preferably at least 1.8 N, and more preferably atleast 2.2 N when the concentration of the methylcellulose is from 0.2 to0.4 weight percent,

ii) at least 2.0 N, preferably at least 2.5 N, and more preferably atleast 3.0 N when the concentration of the methylcellulose is from 0.5 to0.7 weight percent,

iii) at least 2.5 N, preferably at least 3.0 N, and more preferably atleast 3.5 N when the concentration of the methylcellulose is from 0.8 to1.0 weight percent,

iv) at least 3.5 N, preferably at least 4.5 N, and more preferably atleast 5.0 N when the concentration of the methylcellulose is from 1.1 to1.3 weight percent,

v) at least 4.5 N, preferably at least 5.0 N, and more preferably atleast 6.0 N when the concentration of the methylcellulose is from 1.4 to1.6 weight percent,

vi) at least 9.0 N, preferably at least 10.0 N, and more preferably atleast 11.0 N when the concentration of the methylcellulose is from 1.7to 1.9 weight percent,

vii) at least 11.0 N, preferably at least 12.0 N, and more preferably atleast 13.0 N when the concentration of the methylcellulose is from 2.0to 2.2 weight percent or

viii) at least 13.0 N, preferably at least 14.0 N, and more preferablyat least 15.0 N when the concentration of the methylcellulose is from2.3 to 2.5 weight percent, based on the total weight of the aqueoussolution.

Mathematical rounding rules should be applied to the concentrationsabove. E.g., a concentration of 1.63 or 1.64 weight percent is to beunderstood as 1.6 weight percent, whereas a concentration of 1.65 or1.66 weight percent is to be understood as 1.7 weight percent.

The term “wherein the aqueous solution has a gel fracture forceF_(GF)(37° C.) of . . . ” as used herein means that the aqueous solutionof the methylcellulose gels when it is warmed and after warming to 37°C. has the quoted gel fracture force F_(GF)(37° C.).

Typically the gel fracture force F_(GF)(37° C.) of such aqueous solutionis up to 20 N, more typically up to 15 N when the concentration of themethylcellulose is up to 1.6 weight percent, based on the total weightof the aqueous solution. When the concentration of the methylcelluloseis up to 2.5 weight percent, the gel fracture force F_(GF)(37° C.) istypically up to 75 N, more typically up to 50 N.

In this embodiment of the invention hydroxy groups of anhydroglucoseunits of the methylcellulose are substituted with methyl groups suchthat s23/s26 is 0.27 or less, preferably 0.26 or less, more preferably0.24 or less or even 0.22 or less. In this embodiment of the inventions23/s26 of the methylcellulose typically is 0.08 or more, 0.10 or more,0.12 or more, 0.14 or more, or 0.16 or more. Such aqueous solutions areanother aspect of the present invention. The aqueous solution of suchmethylcellulose has an above-mentioned gel fracture force F_(GF)(37° C.)after warming, even if the aqueous solution of the methylcellulose doesnot comprise any other thickener, gelling agent or ingredient impactingthe fracture force F_(GF)(37° C.) in an amount to increase the gelfracture force F_(GF)(37° C.) or even if the aqueous solution of themethylcellulose does not comprise any amount of other thickener, gellingagent or ingredient impacting the fracture force F_(GF)(37° C.).

The gel fracture force F_(GF)(37° C.) is measured with a TextureAnalyzer (model TA.XTPlus; Stable Micro Systems, 5-Kg load cell) at 37°C. Details of measuring the gel fracture force F_(GF)(37° C.) aredisclosed in the Examples. In vitro gel fracture force of the aqueousgelled solution of methylcellulose having a temperature of 37° C. is aproxy for in vivo gelling. It is quite surprising that due to thehigh-shear process of the present invention i) the gel fracture forceF_(GF)(37° C.) of an aqueous gelled solution comprising anabove-mentioned methylcellulose can be increased without substantiallyincreasing the concentration of the methylcellulose in the solutionand/or that ii) the concentration of the methylcellulose in the solutioncan be decreased without substantially decreasing the gel fracture forceF_(GF)(37° C.) of the aqueous gelled solution. When the concentration ofthe methylcellulose described above is kept constant, the high-shearprocess described above enables the production of an aqueous solutionwhich exhibits an increased gel strength (determined as gel fractureforce) when the aqueous composition reaches the normal body temperatureof an individual. Alternatively, the concentration of themethylcellulose described above in the aqueous solution can be decreasedwhile still maintaining sufficiently high gel strength at the normalbody temperature of an individual.

Another aspect of the present invention is a medicament, food, foodingredient or food supplement which comprises or is made of theabove-mentioned aqueous solution of methylcellulose according to thepresent invention. Without wanting to be bound to the theory, applicantsbelieve that the medicament, food, food ingredient or food supplement ofthe present invention generally forms a gel mass in the individual'sstomach when the medicament, food, food ingredient or food supplement isingested and warmed by an individual. This induces a feeling of satietyin an individual and often causes the individual to reduce its caloricintake.

It is contemplated that, in one embodiment, the medicament, food, foodingredient or food supplement is useful for indications that requiregastric volume to be occupied for at least 60 minutes, preferably atleast 120 minutes, more preferably at least 180 minutes, and mostpreferably at least 240 minutes.

In another embodiment, the medicament is useful for treating gastriculcers, gastro-esophageal reflux disease, or obesity. In a preferredembodiment, the medicament is useful for treating obesity.

Alternatively, in another embodiment, the food, food ingredient or foodsupplement is useful as a slimming aid, weight loss aid, or weightcontrol aid in a non-obese individual, for example for aestheticreasons.

Alternatively, in another embodiment, the medicament, food, foodingredient or food supplement is useful for reducing caloric intake, forinducing satiety or for reversibly reducing stomach void volume in anindividual.

Non-limiting examples of the medicament, food, food ingredient or foodsupplement of the present invention include yogurts, smoothies, drinks,shakes, fruit beverages, beverage shots, sports drinks, and othersolutions, as well as emulsions, including ice creams, creams, mousses,cream cheese, ketchup, spreads, dips, picante, salad dressing,homogenized milk, mayonnaise, gravies, puddings, soups, sauces, sportdrinks and breakfast type cereal products such as porridge.

Preferably the medicament, food, food ingredient or food supplement is ameal replacer or other food product intended to be used in a weight lossor weight control plan.

The present invention provides an effective and convenient method ofproviding good satiety effects to food compositions, especially thoseintended to be used in a weight loss or weight control plan.Furthermore, the products can be manufactured by conventional techniquesand are economical to produce.

Flavoring agents may be added to the medicament, food, food ingredientor food supplement, including varying types of cocoa, pure vanilla orartificial flavour, such as vanillin, ethyl vanillin, chocolate, malt,and mint, extracts or spices, such as cinnamon, nutmeg and ginger, andmixtures thereof. The edible compositions may comprise one or moreconventional colourants, in conventional amounts as desired. Themedicament, food, food ingredient or food supplement may compriseadditional ingredients, such as added vitamins, added minerals, herbs,flavoring agents, antioxidants, preservatives or mixtures thereof.

The aqueous solution of the present invention or the medicament, food,food ingredient or food supplement comprising or being made of theaqueous solution of the present invention is preferably administered atleast 45 minutes, more preferably at least 20 minutes, and mostpreferably, at least 15 minutes, before the individual eats. It ispreferably administered up to 6 hours, more preferably up to 4 hours,and most preferably, up to 2 hours, before the individual eats.

It is understood that the individual's stomach eventually breaks downthe gel mass, allowing it to pass from the stomach into the uppergastrointestinal tract. Naturally occurring mechanisms that break downthe gel mass include physical disruption by stomach mobility anddilution with gastric juices (and consequent reversion to a liquidform). Degradation of gel mass occurs generally within 2 hours,preferably within 4 hours, and more preferably within 6 hours.

A method of making a methylcellulose used in the aqueous solution of thepresent invention is described in more detail in the Examples.Generally, cellulose pulp is treated with a caustic, for example analkali metal hydroxide. Preferably, about 1.5 to about 3.0 mol NaOH permol of anhydroglucose units in the cellulose is used. Uniform swellingand alkali distribution in the pulp is optionally controlled by mixingand agitation. The rate of addition of aqueous alkaline hydroxide isgoverned by the ability to cool the reactor during the exothermicalkalization reaction. In one embodiment, an organic solvent such asdimethyl ether is added to the reactor as a diluent and a coolant.Likewise, the headspace of the reactor is optionally purged with aninert gas (such as nitrogen) to minimize unwanted reactions with oxygenand molecular weight losses of the methylcellulose. In one embodiment,the temperature is maintained at or below 45° C.

A methylating agent, such as methyl chloride, is also added byconventional means to the cellulose pulp, either before, after, orconcurrent with the caustic, generally in an amount of 2.0 to 3.5 molmethylating agent per mol of anhydroglucose units in the cellulose.Preferably, the methylating agent is added after the caustic. Once thecellulose has been mixed with caustic and methylating agent, thereaction temperature is increased to about 75° C. and reacted at thistemperature for about half an hour.

In a preferred embodiment, a staged addition is used, i.e., a secondamount of caustic is added to the mixture over at least 30 minutes,preferably at least 45 minutes, while maintaining the temperature atleast 55° C., preferably a least 65° C. Preferably, 2 to 4 mol causticper mol of anhydroglucose units in the cellulose is used. A stagedsecond amount of methylating agent is added to the mixture, eitherbefore, after, or concurrent with the caustic, generally in an amount of2 to 4.5 mol methylating agent per mol of anhydroglucose units in thecellulose. Preferably, the second amount of methylating agent is addedprior to the second amount of caustic.

The methylcellulose is washed to remove salt and other reactionby-products. Any solvent in which salt is soluble may be employed, butwater is preferred. The methylcellulose may be washed in the reactor,but is preferably washed in a separate washer located downstream of thereactor. Before or after washing, the methylcellulose may be stripped byexposure to steam to reduce residual organic content. The celluloseether may subsequently be subjected to a partial depolymerizationprocess. Partial depolymerization processes are well known in the artand described, for example, in European Patent Applications EP1,141,029; EP 210,917; EP 1,423,433; and U.S. Pat. No. 4,316,982.Alternatively, partial depolymerization can be achieved during theproduction of the cellulose ethers, for example by the presence ofoxygen or an oxidizing agent.

The methylcellulose is dried to a reduced moisture and volatile contentof preferably 0.5 to 10.0 weight percent water and more preferably 0.8to 5.0 weight percent water and volatiles based upon the weight ofmethylcellulose. The reduced moisture and volatile content enables themethylcellulose to be milled into particulate form. The methylcelluloseis milled to particulates of desired size. If desired, drying andmilling may be carried out simultaneously.

Some embodiments of the invention will now be described in detail in thefollowing Examples.

EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. Inthe Examples the following test procedures are used.

Production of Methylcellulose MC-I

Methylcellulose MC-I is produced according to the following procedure.Finely ground wood cellulose pulp is loaded into a jacketed, agitatedreactor. The reactor is evacuated and purged with nitrogen to removeoxygen, and then evacuated again. The reaction is carried out in twostages. In the first stage, a 50 weight percent aqueous solution ofsodium hydroxide is sprayed onto the cellulose until the level reaches1.8 mol of sodium hydroxide per mol of anhydroglucose units of thecellulose, and then the temperature is adjusted to 40° C. After stirringthe mixture of aqueous sodium hydroxide solution and cellulose for about20 minutes at 40° C., 1.5 mol of dimethyl ether and 2.3 mol of methylchloride per mol of anhydroglucose units are added to the reactor. Thecontents of the reactor are then heated in 60 min to 80° C. After havingreached 80° C., the first stage reaction is allowed to proceed for 5min. Then the reaction is cooled down to 65° C. in 20 min.

The second stage of the reaction is started by addition of methylchloride in an amount of 3.4 molar equivalents of methyl chloride permol of anhydroglucose unit. The addition time for methyl chloride is 20min. Then a 50 weight percent aqueous solution of sodium hydroxide at anamount of 2.9 mol of sodium hydroxide per mol of anhydroglucose units isadded over a time period of 45 min. The rate of addition is 0.064 mol ofsodium hydroxide per mol of anhydroglucose units per minute. After thesecond-stage addition is completed the contents of the reactor areheated up to 80° C. in 20 min and then kept at a temperature of 80° C.for 120 min.

After the reaction, the reactor is vented and cooled down to about 50°C. The contents of the reactor are removed and transferred to a tankcontaining hot water. The crude MC-I is then neutralized with formicacid and washed chloride free with hot water (assessed by AgNO₃flocculation test), cooled to room temperature and dried at 55° C. in anair-swept drier, and subsequently ground.

The methylcellulose MC-I has a DS(methyl) of 1.88 (30.9 wt. % methoxyl),a mol fraction (26-Me) of 0.3276±0.0039, a mol fraction (23-Me) of0.0642±0.0060, an s23/s26 of 0.20±0.02, a steady-shear-flow viscosityη(5° C., 10 s⁻¹, 2 wt. % MC) of 5500 mPa·s, and a gelation temperatureof 28° C. The properties of the methylcellulose MC-I are measured asdescribed below.

Methylcellulose MC-II

A methylcellulose was used which is commercially available from The DowChemical Company under the Trademark Methocel™ SGA16M cellulose etherwhich has a DS(methyl) of 1.9 (about 31 wt. % methoxyl), an s23/s26between 0.27 and 0.32 and a viscosity of about 16000 mPa·s, determinedas a 2.0% by weight solution in water at 20° C.±0.1° C. by an Ubbelohdeviscosity measurement according to DIN 51562-1:1999-01 (January 1999).

Determination of the DS(Methyl) of Methylcellulose

The determination of the % methoxyl in methylcellulose is carried outaccording to the United States Pharmacopeia (USP34). The values obtainedare % methoxyl. These are subsequently converted into degree ofsubstitution (DS) for methyl substituents. Residual amounts of salt aretaken into account in the conversion.

Determination of the Gelation Temperature of Aqueous Methylcellulose

Aqueous methylcellulose solutions are subjected to small-amplitudeoscillatory shear flow (frequency=2 Hz, strain amplitude=0.5%) whilewarming from 5 to 85° C. at 1 K/min in a rotational rheometer (AntonPaar, MCR 501, Peltier temperature-control system). The oscillatoryshear flow is applied to the sample placed between parallel-platefixtures (type PP-50; 50-mm diameter, 1-mm separation [gap]). Water lossto the sheared material is minimized during the temperature ramp by (1)covering the fixtures with a metal ring (inner diameter of 65 mm, widthof 5 mm, height of 15 mm) and (2) placing a water-immiscible paraffinoil around the sample perimeter. The storage modulus G′, which isobtained from the oscillation measurements, represents the elasticproperties of the solution (during the gelation process ofmethylcellulose, G′ increases). The loss modulus G″, which is obtainedfrom the oscillation measurements, represents the viscous properties ofthe solution. The low strain amplitude is in the linear viscoelasticregime to ensure that the applied shear flow does not create or destroystructure in the aqueous methylcellulose materials. The gelationtemperature, T_(gel), is identified as the temperature when G′ and G″are equal (e.g. T_(gel)=T(G′=G″).

Determination of the Gel Puncture Force

The gel puncture force is measured with a Texture Analyzer (model TA.XT2Stable Micro Systems, 5-Kg load cell) with a 45° conical probe moving at2 mm/s and at a distance of 15 mm into a cylindrically-shaped gel(height=35 mm, diameter=45 mm) The cylindrically-shaped gel is preparedby placing 80 g of an aqueous solution of methylcellulose in a metalbeaker and covering the beaker with a foil. The beaker is then placed ina pan of boiling water for 15 minutes at which point a gel forms. Theexcess liquid that is expulsed from the gel by syneresis is drained outof the beaker, and then the cylindrically-shaped gel is placed ontothree paper towels and tested. Tests are done in triplicate persolution. The cylindrically-shaped gels are tested at 80 C. The averageforces (in gram-force) that are needed to penetrate the gel are given inTable 6. To measure the gel puncture force, the gelatin (Bloom strength)measurement process (ISO 9665) is used which provides the force valuesin gram (g).

Determination of the Viscosity of Aqueous Methylcellulose

The steady-shear-flow viscosity η(5° C., 10 s⁻¹, 2 wt. % MC) of anaqueous 2-wt. % methylcellulose solution is measured at 5° C. at a shearrate of 10 s⁻¹ with an Anton Paar Physica MCR 501 rheometer andcone-and-plate sample fixtures (CP-50/1, 50-mm diameters).

Determination of the Gel Fracture Force F_(GF)(37° C.) of aMethylcellulose

Cylindrically-shaped gels (height=20 mm, diameter=20 mm) are fabricatedby introducing about 6.5 g of an aqueous solution of methylcellulosehaving a temperature of about 5° C. into a syringe (20-mL volume,NORM-JECT Luer, one end cut off above the needle port), sealing the cutend with glass, and placing the syringe in a constant-temperature waterbath (set at 39.5° C.) for one hour.

The gel fracture force F_(GF)(37° C.) is measured with a TextureAnalyzer (model TA.XTPlus; Stable Micro Systems, 5-Kg load cell) locatedinside a cabinet (model XT/TCH Stable Micro Systems, Surrey, UK)designed to hold the temperature at 37.0° C. The cylindrically-shapedgels are compressed between two plates (50-mm-diameter, platecompression rate=10 mm/s, trigger force=0.5 g, maximum distance=18 mm)within about two to three minutes after removal from the 39.5° C. waterbath. The plate displacement [mm] and compression force [N] is measuredat selected time intervals (400 points/s) until the gel collapses. Themaximum compressional force, measured prior to the gel collapse, isidentified as F_(GF)(37° C.). The results of six replicates aretypically averaged and the average results reported in units of Newton.

Determination of s23/s26 of Methylcellulose

The approach to measure the ether substituents in methylcellulose isgenerally known. See for example the approach described in principle forEthyl Hydroxyethyl Cellulose in Carbohydrate Research, 176 (1988)137-144, Elsevier Science Publishers B.V., Amsterdam, DISTRIBUTION OFSUBSTITUENTS IN O-ETHYL-O-(2-HYDROXYETHYL)CELLULOSE by Bengt Lindberg,Ulf Lindquist, and Olle Stenberg.

Specifically, determination of s23/s26 was conducted as follows: 10-12mg of the methylcellulose were dissolved in 4.0 mL of dryanalytical-grade dimethyl sulfoxide (DMSO) (Merck, Darmstadt, Germany,stored over 0.3 nm molecular sieve beads) at about 90° C. with stirringand then cooled to room temperature. The solution was stirred at roomtemperature over night to ensure complete solubilization/dissolution.The entire perethylation including the solubilization of themethylcellulose was performed using a dry nitrogen atmosphere in a 4 mLscrew cap vial. After solubilization, the dissolved methylcellulose wastransferred to a 22-mL screw-cap vial to begin the perethylationprocess. Powdered sodium hydroxide (freshly pestled, analytical grade,Merck, Darmstadt, Germany) and ethyl iodide (for synthesis, stabilizedwith silver, Merck-Schuchardt, Hohenbrunn, Germany) were introduced in athirty-fold molar excess relative to the level of anhydroglucose unitsin the methylcellulose, and the mixture was vigorously stirred undernitrogen in the dark for three days at ambient temperature. Theperethylation was repeated with addition of the threefold amount of thereagents sodium hydroxide and ethyl iodide compared to the first reagentaddition, and stirring at room temperature was continued for anadditional two days. Optionally, the reaction mixture could be dilutedwith up to 1.5 mL DMSO to ensure good mixing during the course of thereaction. Next, five mL of 5% aqueous sodium thiosulfate solution waspoured into the reaction mixture, and the mixture was then extractedthree times with 4 mL of dichloromethane. The combined extracts werewashed three times with 2 mL of water. The organic phase was dried withanhydrous sodium sulfate (about 1 g). After filtration, the solvent wasremoved with a gentle stream of nitrogen, and the sample was stored at4° C. until needed.

Hydrolysis of about 5 mg of the perethylated samples was performed undernitrogen in a 2-mL screw-cap vial with 1 mL of 90% aqueous formic acidunder stirring at 100° C. for 1 hour. The acid was removed in a streamof nitrogen at 35-40° C. and the hydrolysis was repeated with 1 mL of 2Maqueous trifluoroacetic acid for 3 hours at 120° C. in an inert nitrogenatmosphere with stirring. After completion, the acid was removed todryness in a stream of nitrogen at ambient temperature using ca. 1 mL oftoluene for co-distillation.

The residues of the hydrolysis were reduced with 0.5 mL of 0.5-M sodiumborodeuteride in 2N aqueous ammonia solution (freshly prepared) for 3hours at room temperature with stirring. The excess reagent wasdestroyed by dropwise addition of about 200 μL of concentrated aceticacid. The resulting solution is evaporated to dryness in a stream ofnitrogen at about 35-40° C. and subsequently dried in vacuum for 15 minat room temperature. The viscous residue was dissolved in 0.5 mL of 15%acetic acid in methanol and evaporated to dryness at room temperature.This was done five times and repeated four additional times with puremethanol. After the final evaporation, the sample was dried in vacuumovernight at room temperature.

The residue of the reduction was acetylated with 600 μL of aceticanhydride and 150 μL of pyridine for 3 hrs at 90° C. After cooling, thesample vial was filled with toluene and evaporated to dryness in astream of nitrogen at room temperature. The residue was dissolved in 4mL of dichloromethane and poured into 2 mL of water and extracted with 2mL of dichloromethane. The extraction was repeated three times. Thecombined extracts were washed three times with 4 mL of water and driedwith anhydrous sodium sulfate. The dried dichloromethane extract wassubsequently submitted to GC analysis. Depending on the sensitivity ofthe GC system, a further dilution of the extract could be necessary.

Gas-liquid (GLC) chromatographic analyses were performed with Agilent6890N type of gas chromatographs (Agilent Technologies GmbH, 71034Boeblingen, Germany) equipped with Agilent J&W capillary columns (30 m,0.25-mm ID, 0.25-μm phase layer thickness) operated with 1.5-bar heliumcarrier gas. The gas chromatograph was programmed with a temperatureprofile that held constant at 60° C. for 1 min, heated up at a rate of20° C./min to 200° C., heated further up with a rate of 4° C./min to250° C., and heated further up with a rate of 20° C./min to 310° C.where it was held constant for another 10 min. The injector temperaturewas set to 280° C. and the temperature of the flame ionization detector(FID) was set to 300° C. Exactly 1 μL of each sample was injected in thesplitless mode at 0.5-min valve time. Data were acquired and processedwith a LabSystems Atlas work station.

Quantitative monomer composition data were obtained from the peak areasmeasured by GLC with FID detection. Molar responses of the monomers werecalculated in line with the effective carbon number (ECN) concept butmodified as described in the table below. The effective carbon number(ECN) concept has been described by Ackman (R. G. Ackman, J. GasChromatogr., 2 (1964) 173-179 and R. F. Addison, R. G. Ackman, J. GasChromatogr., 6 (1968) 135-138) and applied to the quantitative analysisof partially alkylated alditol acetates by Sweet et. al (D. P. Sweet, R.H. Shapiro, P. Albersheim, Carbohyd. Res., 40 (1975) 217-225).

ECN Increments Used for ECN Calculations:

Type of carbon atom ECN increment hydrocarbon 100 primary alcohol 55secondary alcohol 45

In order to correct for the different molar responses of the monomers,the peak areas were multiplied by molar response factors MRFmonomerwhich are defined as the response relative to the 2,3,6-Me monomer. The2,3,6-Me monomer were chosen as reference since it was present in allsamples analyzed in the determination of s23/s26.MRFmonomer=ECN2,3,6-Me/ECNmonomer

The mol fractions of the monomers were calculated by dividing thecorrected peak areas by the total corrected peak area according to thefollowing formulas:

(1) s23 is the sum of the molar fractions of anhydroglucose units whichmeet the following condition [the two hydroxy groups in the 2- and3-positions of the anhydroglucose unit are substituted with methylgroups, and the 6-position is not substituted (=23-Me)]; and(2) s26 is the sum of the molar fractions of anhydroglucose units whichmeet the following condition [the two hydroxy groups in the 2- and6-positions of the anhydroglucose unit are substituted with methylgroups, and the 3-position is not substituted (=26-Me)].

Example 1

An aqueous solution of the methylcellulose MC-I was prepared by adding acorresponding amount of the dry methylcellulose powder to water whichhad an initial temperature of 25° C. using a Yamato LT 400 lab overheadmixer having a rotor diameter of 63.5 mm and a gap distance between theouter diameter of the rotor and the stationary of 10.16 mm and runningat 500 rpm, which resulted in a shear rate of 164 s⁻¹, to achieve a gooddispersion. The mixture of the methylcellulose MC-I and the water wascooled to 2° C. within 20 minutes while stirring at the same speed.After the mixture of methylcellulose MC-I and water reached thetemperature of 2° C., the mixture was subjected to high shear using aSilverson L4-R high-shear mixer (rotor stator) running at 5000 rpmresulting in a shear rate of 56070 s⁻¹ for 5 minutes. The Silverson L4-Rhigh-shear mixer was equipped with a square hole high shear screen andhad a rotor diameter of 38.1 mm and a gap of 0.178 mm.

The gel fracture force F_(GF)(37° C.) was measured immediately after thepreparation of the aqueous solution of the methylcellulose MC-I andafter storage of the aqueous solution for 1 day at 4° C.

Comparative Example A

An aqueous solution of the methylcellulose MC-I was substantiallyprepared as described in WO2011/139763 to obtain an aqueous solution ofmethylcellulose MC-I. A corresponding amount of dried methylcellulosepowder was added to water which had an initial temperature of 25° C.using a Yamato LT 400 lab overhead mixer having a rotor diameter of 63.5mm and a gap distance between the outer diameter of the propeller andthe stationary of 10.16 mm and running initially at 500 rpm to achieve agood dispersion. The speed of the stirrer was reduced stepwise: 500 rpmfor 15 min, then 400 rpm for 10 min, then 200 rpm for 10 min while theblend was cooled to 2° C., and then 100 rpm for 6 h using the Yamato LT400 lab overhead mixer described above. Stirring at 500 rpm resulted ina shear rate of 164 s⁻¹. The solution was then stored over night at 2°C. without stirring. The gel fracture force F_(GF)(37° C.) wassubsequently measured as described above.

Solutions comprising a concentration of the methylcellulose MC-I inwater as listed in Table 1 below (based on the total weight of thesolution) were produced according to the processes of Example 1 andComparative Example A. The gel fracture forces F_(GF)(37° C.) are listedin Table 1 below.

TABLE 1 MC-I Process of Process of Example 1, F_(GF)(37° C.) concen-Comparative Immediately after tration, Example A, Avg. preparation ofthe After 1 day % F_(GF)(37° C.) aqueous solution storage at 4° C. 1.00.5N 3.5N 3.3N 1.2 1.4N NA 5.4N 1.5 2.0N 6.1N 6.5N 1.8 3.6N NA 8.8N 2.04.5N 12.5N  12.8N  2.1 6.0N NA 15.9N  NA: not assessed

Example 2

The procedure of Example 1 was repeated three times, except that theblend of methylcellulose MC-I and water was cooled to 0.5° C., 5° C. or10° C. instead of cooling it to 2° C. The amount of methylcellulose MC-Iwas chosen to produce a 1.5% solution of MC-I, based on the total weightof the aqueous solution.

Comparative Example B

The procedure of Comparative Example A was repeated, except that theblend of methylcellulose MC-I and water was cooled to 0.5° C. and storedat 0.5° C. instead of cooling it to 2° C. The amount of methylcelluloseMC-I was chosen to produce a 1.5% solution of MC-I, based on the totalweight of the aqueous solution. Cooling such blend only to 5° C. or 10°C. did not result in a sufficient gel fracture force F_(GF)(37° C.).

The gel fracture forces F_(GF)(37° C.) of the solutions producedaccording to Example 2 and Comparative Example B are listed in Table 2below.

TABLE 2 Process of Example 2, Process of Average F_(GF)(37° C.)Hydration Comparative Immediately after temperature, Example B, Avg.preparation of the After 1 day ° C. F_(GF)(37° C.) aqueous solutionstorage at 4° C. 0.5 3.5N 10.1N  10.3N  2  2N 6.1N 6.5N 5 — 4.7N 4.9N 10— 2.1N 2.2N

Example 3 and Comparative Example C

The procedures of Example 1 and of Comparative Example A were repeated,except that the blend of methylcellulose MC-I and water was cooled to0.5° C. instead of cooling it to 2° C. The amount of methylcelluloseMC-I was chosen to produce a 2.0% solution of MC-I, based on the totalweight of the aqueous solution. The gel fracture forces F_(GF)(37° C.)of the produced solutions are listed in Table 3 below.

TABLE 3 Process of Example 3, Process of Average F_(GF)(37° C.)Hydration Comparative Immediately after temperature, Example C, Avg.preparation of the After 1 day ° C. F_(GF)(37° C.) aqueous solutionstorage at 4° C. 0.5 7.9N 23.2N 24.8N 2 5.0N 12.5N 12.8N

The results in Tables 1, 2 and 3 illustrate that the process of thepresent invention provides an aqueous solution of an above describedmethylcellulose of much higher gel strength than the known process asdisclosed in WO2011/139763 when the blend of water and themethylcellulose in both processes has the same concentration ofmethylcellulose and is cooled to the same temperature. Alternatively, alower concentration of methylcellulose or less cooling is needed in theprocess of the present invention to achieve an aqueous solution ofmethylcellulose of the same gel strength as in the prior art process.

Comparative Example D

A 2% aqueous solution of the methylcellulose MC-I was prepared asdescribed in the Examples of the co-pending International PatentApplication PCT/US12/059714, filed 11 Oct. 2012. To obtain the 2%aqueous solution of methylcellulose MC-I, 3 g of milled, ground, anddried methylcellulose MC-I (under consideration of the water content ofthe methylcellulose) were added to 147 g of tap water (temperature20-25° C.) at room temperature while stirring with an overhead labstirrer at 750 rpm with a 3-wing (wing=2 cm) blade stirrer in a beakerof 60 mm inner diameter. The rotor diameter of the stirrer was 40 mm andthe gap distance between the outer diameter of the rotor and thestationary was 10 mm. The shear rate was 157 s⁻¹. The solution was thencooled to about 1.5° C. After the temperature of 1.5° C. was reached,the solution was stirred for 180 min at 750 rpm. Prior to analysis, thesolution was stirred for 15 min at 100 rpm in an ice bath. The gelfracture force F_(GF)(37° C.) was subsequently measured as describedabove. As disclosed in Table 2, Comparative Example C-1 of theco-pending International Patent Application PCT/US12/059714, the gelfracture force F_(GF)(37° C.) was 8.6±1.1.

The comparison between Example 3 and Comparative Example D alsoillustrates that the process of the present invention provides anaqueous solution of an above described methylcellulose of much highergel strength than a low-shear process when the blend of water andmethylcellulose in both processes has the same concentration ofmethylcellulose and is cooled to essentially the same temperature.

Example 4

The procedure of Example 1 was repeated 6 times, except that the blendof methylcellulose MC-I and water was subjected to high shear using thesame Silverson L4-R high-shear mixer as in Example 1, but the high-shearmixer was caused to run at a mixing speed as listed in Table 4. Thechosen mixing speeds in the chosen device corresponded to the shearrates listed in Table 4. The blend of methylcellulose MC-I and water wascooled to 2° C. The amount of methylcellulose MC-I was chosen to producea 1.5% solution of MC-I, based on the total weight of the aqueoussolution.

TABLE 4 Average Gel fracture force, N Immediately after preparation ofthe After 1 day Mixing speed, rpm Shear rate, s−1 aqueous solutionstorage at 4° C. 1000 11210 2.7 2.8 2000 22430 3.8 3.6 3000 33640 4.64.5 4000 44860 6.5 6.6 5000 56070 6.3 6.4 6000 67280 6.4 6.3

Example 5

The procedure of Example 1 was repeated, except that the blend ofmethylcellulose MC-I and water was subjected to high shear using thesame Silverson L4-R high-shear mixer as in Example 1 running at 5000 rpm(resulting in a shear rate of 56070 s⁻¹) for 1 minute, 2 minutes or 3minutes respectively instead of subjecting it to high shear for 5minutes at 2° C. The amount of methylcellulose MC-I was chosen toproduce a 1.5% solution of MC-I, based on the total weight of theaqueous solution. The results in Table 5 below list the average of 4measurements each.

TABLE 5 High-shearing Average Gel fracture force, N (56070 s⁻¹) atImmediately after preparation After 1 day 5000 rpm for x minutes of theaqueous solution storage at 4° C. 1 minute  6.1N 6.2N 2 minutes 6.5N6.0N 3 minutes 6.3N 6.1N 5 minutes 6.0N 6.2N

Example 6

An aqueous solution of the methylcellulose MC-II was prepared by adding1.5 wt. % of the dry methylcellulose MC-II powder to water which had aninitial temperature of 40° C. using the same Yamato LT 400 lab overheadmixer as in Comparative Example A running at 500 rpm to achieve a gooddispersion. The mixture of methylcellulose MC-II and water was cooled toa corresponding temperature listed in Table 6 below within 10 to 20minutes while stirring at the same speed. After the mixture of themethylcellulose MC-II and the water reached the temperature listed inTable 6 below, the mixture was subjected to high shear using the sameSilverson L4-R high-shear mixer as in Example 1 running at 5000 rpm(resulting in a shear rate of 56070 s⁻¹) for 5 minutes.

The gel puncture force was measured immediately after the preparation ofthe aqueous solution of the methylcellulose MC-II and after storage ofthe aqueous solution for 1 day at the temperature listed in Table 6.

Comparative Example E

An aqueous solution of the methylcellulose MC-II was prepared by adding1.5 wt. % of dry methylcellulose MC-II powder, based on total weight ofthe aqueous solution, to water which had an initial temperature of 40°C. using the same Yamato LT 400 lab overhead mixer as in ComparativeExample A running at 500 rpm (shear rate of 164 s⁻¹) to achieve a gooddispersion. The mixture of methylcellulose MC-II and water was cooled toa temperature as listed in Table 6 below within 10 to 20 minutes whilestirring at the same speed. The stirring was continued at thetemperature listed in Table 6 below for three hours. The solution wasthen stored over night at a corresponding temperature as listed in Table6 without stirring. The gel puncture force was subsequently measured asdescribed above.

TABLE 6 Process of Example 6, Hydration gel puncture force and storageProcess of Comp. Immediately after temperature, Example E, gelpreparation of the After 1 day ° C. puncture force aqueous solutionstorage 5 291 g (2.85N) 298 g (2.92N) 297 g (2.91N) 10 281 g (2.76N) 291g (2.85N) 293 g (2.87N) 15 138 g (1.35N) 273 g (2.67N) 270 g (2.64N) 20 93 g (0.91N) 236 g (2.31N) 241 g (2.36N)

The results in Table 6 illustrate that in the high-shear process of thepresent invention an aqueous solution of the methylcellulose MC-II ofreasonably high gel puncture force is even obtained at a temperature of15 to 20° C. In a known low-shear process at such temperature an aqueoussolution of the methylcellulose MC-II is obtained which has a much lowergel puncture force.

Without wanting to be bound by the theory, it is believed that thebiggest advantages of the process of the present invention, as comparedto known low-shear processes, are achieved at temperatures of about 15to 25° C. below the gelation temperature of the above-describedmethylcellulose.

Example 7

An aqueous solution of the methylcellulose MC-I and sodium chloride wasprepared by adding 1.5 weight percent of the dry methylcellulose powderto an aqueous solution of sodium chloride which had an initialtemperature of 25° C. using a the same Yamato LT 400 lab overhead mixeras in Comparative Example A running at 500 rpm to achieve a gooddispersion. The concentration of the sodium chloride is listed in Table7 below. The concentrations of sodium chloride and of themethylcellulose MC-I are based on the total weight of the aqueoussolution. The mixture of the methylcellulose MC-I, the sodium chlorideand the water was cooled to 2° C. within 20 minutes while stirring atthe same speed. After the mixture of methylcellulose MC-I, sodiumchloride and water reached the temperature of 2° C., the mixture wassubjected to high shear using the same Silverson L4-R high-shear mixeras in Example 1, which was running at 5000 rpm (resulting in a shearrate of 56070 s⁻¹) for 5 minutes. For comparative purposes an aqueoussolution of 1.5 wt. % of methylcellulose MC-I in water in the absence ofsodium chloride was prepared in the same manner. The gel fracture forceF_(GF)(37° C.) was measured after storage of the aqueous solution for 1day at 4° C.

Comparative Example F

An aqueous solution of methylcellulose MC-I and sodium chloride wasprepared by adding 1.5 weight percent of the dry methylcellulose powderto an aqueous solution of sodium chloride. The concentration of thesodium chloride is listed in Table 7 below. The concentrations of sodiumchloride and of methylcellulose MC-I are based on the total weight ofthe aqueous solution. The aqueous solution was substantially prepared asdescribed in WO2011/139763. The dried methylcellulose powder was addedto the aqueous solution of sodium chloride which had an initialtemperature of 25° C. using the same Yamato LT 400 lab overhead mixer asin Comparative Example A running initially at 500 rpm to achieve a gooddispersion. The speed of the stirrer was reduced stepwise: 500 rpm for15 min, then 400 rpm for 10 min, then 200 rpm for 10 min while the blendwas cooled to 2° C., and then 100 rpm for 6 h using the same Yamato LT400 lab overhead mixer described above. Stirring at 500 rpm resulted ina shear rate of 164 s⁻¹. The solution was then stored over night at 2°C. without stirring. For comparative purposes an aqueous solution of 1.5wt. % of methylcellulose MC-I in water in the absence of sodium chloridewas prepared in the same manner. The gel fracture force F_(GF)(37° C.)was subsequently measured as described above.

TABLE 7 sodium chloride Process of Comparative Process of Example 7,concentration, Example F, Average F_(GF)(37° C.), N wt. % AverageF_(GF)(37° C.), N After 1 day storage at 4° C. 0 2.0 6.1 2.0 1.8 7.1 5.01.0 5.8

The invention claimed is:
 1. A process for preparing an aqueous solutionof a methylcellulose having anhydroglucose units joined by 1-4 linkageswherein hydroxy groups of anhydroglucose units are substituted withmethyl groups such that s23/s26 is 0.36 or less, wherein s23 is themolar fraction of anhydroglucose units wherein only the two hydroxygroups in the 2- and 3-positions of the anhydroglucose unit aresubstituted with methyl groups and s26 is the molar fraction ofanhydroglucose units wherein only the two hydroxy groups in the 2- and6-positions of the anhydroglucose unit are substituted with methylgroups, wherein the process comprises the step of mixing themethylcellulose with an aqueous liquid at a shear rate of at least 1000s⁻¹.
 2. The process of claim 1 wherein an aqueous solution comprisingfrom 0.2 to 2.5 percent of the methylcellulose is prepared, based on thetotal weight of the aqueous solution.
 3. The process of claim 1, whereinthe viscosity of the methylcellulose is from 200 to 10000 mPa·s, whenmeasured as a 2 wt. % solution in water at 5° C. at a shear rate of 10s⁻¹.
 4. The process of claim 1 comprising the step of mixing amethylcellulose, wherein hydroxy groups of anhydroglucose units aresubstituted with methyl groups such that s23/s26 is 0.27 or less, withthe aqueous liquid at a temperature of not higher than 10° C.
 5. Theprocess of claim 1 comprising the step of mixing a methylcellulose,wherein hydroxy groups of anhydroglucose units are substituted withmethyl groups such that s23/s26 is 0.27 or less, with an aqueous liquidat a temperature of from 11° C. to 23° C.
 6. The process of claim 1,wherein an aqueous solution is prepared comprising from 0.2 to 2.5percent of the methylcellulose (MC) and having a gel fracture forceF_(GF)(37° C.) of i) at least 1.4 N when the MC concentration is from0.2 to 0.4 percent, ii) at least 2.0 N when the MC concentration is from0.5 to 0.7 percent, iii) at least 2.5 N when the MC concentration isfrom 0.8 to 1.0 percent, iv) at least 3.5 N when the MC concentration isfrom 1.1 to 1.3 percent, v) at least 4.5 N when the MC concentration isfrom 1.4 to 1.6 percent, vi) at least 9.0 N when the MC concentration isfrom 1.7 to 1.9 percent, vii) at least 11.0 N when the MC concentrationis from 2.0 to 2.2 percent, or viii) at least 13.0 N when the MCconcentration is from 2.3 to 2.5 percent, based on the total weight ofthe aqueous solution and having a gel fracture force F_(GF)(37° C.) ofup to 20 N when the MC concentration is up to 1.6 percent and a gelfracture force F_(GF)(37° C.) of up to 75 N when the MC concentration isup to 2.5 percent.